Advancing biological and clinical applications of genomic Minimal Residual Disease detection in AML

推进基因组微小残留病检测在 AML 中的生物学和临床应用

基本信息

  • 批准号:
    9763499
  • 负责人:
  • 金额:
    $ 41.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Acute myelogenous leukemia (AML) affects more than 20,000 adult patients in the US per year causing greater than 11,000 untimely deaths. Standard AML therapy comprises chemotherapy induction to achieve leukemia debulking, followed by a few cycles of consolidation chemotherapy alone and/or followed by allogeneic bone marrow transplantation. This general therapeutic approach to AML is risk-adapted relying principally on well-established prognostic factors, including the type of AML, age, gene mutations and cytogenetic results. Despite best efforts, AML remains incurable in the majority of afflicted patients. A principle barrier to AML cure is disease relapse despite achieving a clinical complete remission (CR) following standard chemotherapy regimens. Of substantial interest therefore, is the identification and accurate measurement of residual AML that persists during remission in AML patients, as such residual disease is likely the source of relapse. Several important questions about AML relapse are only in early stages of satisfactory answers, including i) how to best measure minimal residual disease (MRD) in AML, ii) whether all MRD is indeed caused by residual disease or rather as suggested by recent data comprises a mixture of leukemia, pre- leukemia and age-related clonal hematopoiesis, iii) what constitutes the cellular source of relapse in AML, iv) if such relapse-causing cells can be better targeted using novel therapeutic approaches, and v) under what circumstances is MRD prognostic and useful for MRD risk-adapted AML clinical management. Given lack of well-suited techniques to reliably answer the relevant questions detailed above, we have optimized droplet digital PCR (ddPCR), a novel ultra-high sensitivity assay for detecting genomic MRD in AML. In a detailed recently published study (Parkin et al, JCI 2017) we found that AML frequently relapses from rare cells residing in remission marrows that based on mutation analysis resemble AML blast cells detected at diagnosis. We demonstrated the feasibility for detecting AML-associated gene mutations at allele frequencies as low as 0.002% and have also provided important novel prognostic insights. In this application, we are proposing complete characterization of mutational MRD and aberrant cellular clusters in AML remission bone marrows using a combination of sophisticated cell sorting and single cell transcriptome analyses complemented with mouse xenografting and ex vivo colony forming assays. Anticipated findings will improve the functional characterization of cells that carry AML-associated gene mutations in an attempt to identify and better characterize the source(s) of AML relapse. Using AML samples from two clinical validation cohorts, we will define the prognostic utility of ddPCR-based MRD assessments. Overall, data will lay the foundation for future real-time genomic MRD-guided clinical AML trials aiming at monitoring and improving consolidation and maintenance therapy and ultimately survival outcome in AML.
抽象的 急性骨髓性白血病(AML)每年影响20,000多名成年患者,导致更大 超过11,000人过早死亡。标准AML疗法包括化学疗法诱导以实现 白血病降临,然后是几个单独的巩固化学疗法和/或接和/或 同种异体骨髓移植。这种对AML的一般治疗方法是适应风险的 主要是基于公认的预后因素,包括AML的类型,年龄,基因突变和 细胞遗传学结果。尽管竭尽全力,但大多数患者中的AML仍然无法治愈。一个 AML治愈的主要障碍是疾病复发,尽管在 标准化疗方案。因此,具有实质性的识别和准确是 在AML患者缓解过程中持续存在的残留AML的测量,因为这种残留疾病很可能 复发的来源。关于AML复发的几个重要问题仅在令人满意的早期阶段 答案,包括i)如何最好地测量AML中最小残留疾病(MRD),ii) 确实是由残留疾病引起的,或者是最近数据所暗示的,包括白血病的混合物 白血病和与年龄相关的克隆造血作用,iii)构成AML复发的构成的原因,iv),如果 使用新型的治疗方法可以更好地针对这种引起复发的细胞,v) 情况是MRD预后的,对于适应MRD风险的AML临床管理有用。 鉴于缺乏适合可靠回答上面详述的相关问题的技术,我们已经 优化的液滴数字PCR(DDPCR),这是一种用于检测基因组MRD的新型超高灵敏度测定 AML。在一项详细的最近发表的研究(Parkin等,JCI 2017)中,我们发现AML经常复发 从居住在缓解骨髓中的稀有细胞中,基于突变分析类似于AML爆炸细胞 在诊断时检测到。我们证明了在等位基因检测AML相关基因突变的可行性 频率低至0.002%,还提供了重要的新型预后见解。 在此应用中,我们提出了突变MRD和异常细胞的完整表征 AML缓解骨髓中的簇使用复杂的细胞分选和单细胞的组合 转录组分析与小鼠异种法和体内菌落形成测定法相辅相成。预期 发现将改善携带与AML相关基因突变的细胞的功能表征 尝试识别和更好地表征AML复发的来源。使用来自两个临床的AML样品 验证队列,我们​​将定义基于DDPCR的MRD评估的预后效用。总体而言,数据将 为未来实时基因组引导的临床AML试验奠定了基础,旨在监视和 改善AML的合并和维持疗法,并最终在AML中生存结果。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据

数据更新时间:2024-06-01

Sami Nimer Malek的其他基金

The Biology of Mutant STAT6 in Follicular Lymphoma
滤泡性淋巴瘤中突变 STAT6 的生物学
  • 批准号:
    10368629
    10368629
  • 财政年份:
    2022
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
The Biology of Mutant STAT6 in Follicular Lymphoma
滤泡性淋巴瘤中突变 STAT6 的生物学
  • 批准号:
    10683966
    10683966
  • 财政年份:
    2022
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Advancing biological and clinical applications of genomic Minimal Residual Disease detection in AML
推进基因组微小残留病检测在 AML 中的生物学和临床应用
  • 批准号:
    10474636
    10474636
  • 财政年份:
    2018
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
The genomic pathogenesis of Follicular Lymphoma
滤泡性淋巴瘤的基因组发病机制
  • 批准号:
    9002028
    9002028
  • 财政年份:
    2015
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia
慢性淋巴细胞白血病的基因组复杂性和临床结果
  • 批准号:
    7714457
    7714457
  • 财政年份:
    2009
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia
慢性淋巴细胞白血病的基因组复杂性和临床结果
  • 批准号:
    8053248
    8053248
  • 财政年份:
    2009
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia
慢性淋巴细胞白血病的基因组复杂性和临床结果
  • 批准号:
    8450207
    8450207
  • 财政年份:
    2009
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia
慢性淋巴细胞白血病的基因组复杂性和临床结果
  • 批准号:
    8253756
    8253756
  • 财政年份:
    2009
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Genomic Profiling and clinical Outcome in Chronic Lymphocytic Leukemia
慢性淋巴细胞白血病的基因组分析和临床结果
  • 批准号:
    7303648
    7303648
  • 财政年份:
    2007
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Genomic Profiling and clinical Outcome in Chronic Lymphocytic Leukemia
慢性淋巴细胞白血病的基因组分析和临床结果
  • 批准号:
    7459009
    7459009
  • 财政年份:
    2007
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:

相似国自然基金

儿童期受虐经历影响成年人群幸福感:行为、神经机制与干预研究
  • 批准号:
    32371121
  • 批准年份:
    2023
  • 资助金额:
    50.00 万元
  • 项目类别:
    面上项目
依恋相关情景模拟对成人依恋安全感的影响及机制
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
依恋相关情景模拟对成人依恋安全感的影响及机制
  • 批准号:
    32200888
  • 批准年份:
    2022
  • 资助金额:
    30.00 万元
  • 项目类别:
    青年科学基金项目
生活方式及遗传背景对成人不同生命阶段寿命及死亡的影响及机制的队列研究
  • 批准号:
    82173590
  • 批准年份:
    2021
  • 资助金额:
    56.00 万元
  • 项目类别:
    面上项目

相似海外基金

Targeting Menin in Acute Leukemia with Upregulated HOX Genes
通过上调 HOX 基因靶向急性白血病中的 Menin
  • 批准号:
    10655162
    10655162
  • 财政年份:
    2023
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Exploiting the Metabolic Dependencies of Pediatric AML
利用儿科 AML 的代谢依赖性
  • 批准号:
    10664637
    10664637
  • 财政年份:
    2023
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Clonal hematopoiesis and inherited genetic variation in sickle cell disease
镰状细胞病的克隆造血和遗传变异
  • 批准号:
    10638404
    10638404
  • 财政年份:
    2023
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Integration of epigenetic and non-coding RNA mechanism in leukemia
表观遗传和非编码RNA机制在白血病中的整合
  • 批准号:
    10582327
    10582327
  • 财政年份:
    2023
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别:
Determining the Role and Targeting potential of Serine Metabolism in aggressive sub-types of Acute Myeloid Leukemia
确定丝氨酸代谢在急性髓系白血病侵袭性亚型中的作用和靶向潜力
  • 批准号:
    10659678
    10659678
  • 财政年份:
    2023
  • 资助金额:
    $ 41.69万
    $ 41.69万
  • 项目类别: